In addition to its role in gas exchange, the lung performs nonrespiratory functions including the removal of certain substances from the circulation. Because the liver contains such a great quantity of drug metabolizing enzymes, the lung has been considered relatively unimportant in the total body clearance of substances which are eliminated by metabolism. However, for some xenobiotic agents the rate of substrate delivery to the organ (i.e., blood flow) and not the quantity of degradative enzymes limits metabolic clearance. This perfusion limited model of drug clearance applied to enzyme kinetic data for benzo(a)pyrene, a major toxic component of cigarette smoke, suggests that under certain conditions the lung makes a substantial contribution to the total body clearance of BP. This hypothesis will be tested in isolated livers and lungs of control rats and rats pretreated with 3-methylcholanthrene. Clearance by these organs will also be examined under conditions of hypoxic hypoxia. Since the toxic (i.e., carcinogenic) properties of BP are thought to result from the covalent binding of a metabolically activated intermediate to DNA, the profile of metabolites produced by isolated lung and liver perfused at physiological flows will be examined under the conditions described above. The extent of covalent adduct formation between BP and DNA of lung and liver will also be quantified, and the rate of loss of BP adducts from DNA will be determined. In addition, the extent of BP binding to specific regions (euchromatic vs. heterochromatic and linker vs. core regions) of the genomes from these organs will be determined. Accordingly, this study will assess the role of lung in the total body clearance of BP and will quantify changes in metabolite profile and DNA binding occurring under altered physiological conditions (enzyme induction, hypoxia).